Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. For example, 7TMRs comprise more than 4% of the genes in Caenorhabditis elegans. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, understanding how 7TMRs function is an important goal of biological research. We have used receptors for thyrotropin-releasing hormone (TRH) (TRH-Rs), for thyroid-stimulating hormone (TSH-R) and for free fatty acids (GPR40/FFAR1) as model 7TMRs to study their structure and function. During this year, we have studied several new aspects of the structure and function of these receptors. We gained insight into how agonists act differently at the two subtypes of TRH-Rs, TRH-R1 and TRH-R2, and described TRH analogs with subtype selective activity. Based on models of the TRH-Rs, we developed a hypothesis for the activation of these receptors, that is, how conformational changes lead to receptor activation that could be applicable to all 7TMRs. We began studies of GPR40 to understand the signaling properties of this receptor because it appears to be important in regulation of insulin secretion from pancreatic islets. Lastly, we continued our studies of activation of TSH-R by low molecular weight agonists so as to develop novel ligands for this clinically important 7TMR.